Effect of local hyperthermia on the acute toxicity of misonidazole in mice

SEVERAL recent studies have shown that hyperthermia is able to enhance the direct cytotoxic effect of misonidazole (Bleehen et al., 1978; Hall et al., 1977; Stratford & Adams, 1977; Stone, 1978). These observations led us to investigate the interaction between radiation, hyperthermia and misonidazole (MIS) in an attempt to evaluate the role of such multimodality treatment in experimental tumours. During these experiments we observed an increase in the acute toxicity to mice when heated locally in the presence of MIS. Such a reaction has not previously been described, but as it may have implications for further work in that field, we find it of importance to report here. The increased toxicity was initially observed in mice treated with MIS and local hyperthermia (43-5°C). In this experiment, 14/37 mice died within 2 days of treatment with 0 5 mg/g MIS, injected i.p., 30 min before local hyperthermia was applied to the tumour-bearing leg. Since this was a considerably higher lethality rate than was expected, further toxicological studies were initiated. Ten to twelve-weeks old male and female C3H/Aa mice bred in our own colony were used for LD5o/30d assays. Misonidazole (kindly supplied through Roche Ltd, Denmark, by courtesy of Rud Hammer Jensen) was diluted with isotonic saline to a concentration of 20 mg/ml. This solution was injected i.p. into nonAccepted 27 September 1978